Short-Term Side Effects of Low Dose Valproate Monotherapy in Epileptic Children: A Prospective Study

Objectives Considering the common use of valproate among children, we investigated the short-term side-effects of low dose valproate monotherapy in epileptic children. Materials & Methods In this prospective study, 209 epileptic children (48.3% male, mean age: 7.02 ± 3.13 yr) on low therapeutic dose of valproate monotherapy (20-30 mg/kg/d) were enrolled during 2014-2015 in Isfahan Pediatric Neurology Clinic, Isfahan University of Medical Sciences, Isfahan, Iran and side-effects were evaluated through frequent clinical visits and laboratory tests during 6 months of valproate therapy. Results Weight gain was reported in 53.1% of patients. Decreased appetite was seen in 11% of patients, more frequent in younger cases (P=0.006). Abdominal pain, nausea/vomiting, diarrhea, and constipation were reported in 16.3%, 2.4%, 1.4%, and 1% of patients, respectively. Headache, tremor, dizziness, abnormal color vision, myoclonus, and bruxism were seen in 5.7%, 1.4%, 1%, 1%, 1%, and 0.5% of patients, respectively. Enuresis, hair loss, and skin rash were reported in 8.1%, 6.7%, and 0.5% of patients, respectively. Thrombocytopenia, impaired liver function tests, and leukopenia occurred in 1%, 1%, and 0.5% of patients, respectively. Conclusion Low dose valproate monotherapy may cause numerous side-effects, mostly not life-threatening and requiring no action. Besides more reported complications, we observed decreased appetite (among younger patients), enuresis, and abnormal color vision which are onlybriefly discussed in the literature and need to be addressed more.


Introduction
Valproate (VPA) is a broad-spectrum antiepileptic drug, used for treatment of certain types of seizures since 1970 (1). It can also be used in other conditions including some psychiatric disorders and prophylaxis of migraine (1). Epilepsy is a common disease among children and adolescents.
Approximately 10.5 million children under 15 yr (about 0.8%) suffer from active epilepsy, of whom more than 80% live in developing countries (2). Although VPA is an old antiepileptic drug, it is still widely administered for epileptic patients, since it is favorably safe and inexpensive (3).
VPA may cause transient and non-hazardous side effects as well as serious and life-threatening side effects. Transient and non-hazardous side effects include weight gain, drowsiness, transient hair loss, tremor, increased gamma-glutamyl transferase, nausea, headache, and other complications (1,4). Serious side effects include hepatotoxicity, encephalopathy, coagulation disorders, pancreatitis, and bone marrow suppression (1,5,6). Complications of VPA are also classified as gastrointestinal, neurological, metabolic and endocrine, hematologic, pulmonary, renal, dermatologic, mitochondrial, and hepatic adverse events (1). These complications may be associated with factors such as age and dose (1).
Although several studies were conducted on the subject, no study was designed to evaluate these complications in a pediatric population on low dose VPA as monotherapy. We aimed to investigate the short-term complications of low dose VPA in a pediatric population through frequent interviews, clinical visits, and lab tests during a 6-month period of therapy. time-points: before taking VPA, and after 6 months of taking VPA. As we expected no considerable changes in the children's height and in turn, their body mass index, we calculated weight-for-age Z-score for each subject in these two time-points, using national z-score tables for boys and girls. Two amounts were compared to each other then, and increased z-score for ≥1 unit was considered as weight gain (8).

Materials & Methods
Blood samples were also taken to evaluate complete blood count with differentials (CBC-diff), serum glutamic oxaloacetic transaminase (SGOT), and serum glutamic pyruvic transaminase (SGPT) at four time-points: before starting the medication, 1 month, 3 months, and 6 months after starting the medication. Blood samples were obtained between 8 and 9 in the morning, after an overnight fast and before breakfast. Platelet count <150,000 /µL was considered as thrombocytopenia, WBC <4000 /µL was considered as leukopenia and increased SGOT and SGPT for more than two times were considered as increased liver enzymes. In patients with serious side effects, drug intolerance, and impaired lab tests, VPA was discontinued and was replaced with another drug. All the observed adverse drug reactions were rated using Naranjo scale (9) into one of the categories of highly probable, probable, possible, and doubtful. Naranjo scale determines whether an adverse drug reaction is actually due to the medication or it is caused by other factors. This scale evaluates the probability of a complication through 10 questions (9).
We reported data using descriptive statistics for frequencies and analytical statistics (Mann-Whitney test) for analysis of possible differences, using SPSS 19 (Chicago, IL, USA). A P-value less than 0.05 was considered as significant.

Results
Overall, 229 patients were included initially and 20 of them were excluded (13 patients with worsened seizures and 7 cases who needed higher doses of VPA

Discussion
Weight gain is one of the common complications of VPA seen in 53.1% of our patients, without any association with age. A study on Iranian children showed weight gain due to VPA in 40% of patients (10), however, another study reported weight gain in 58% of their cases (11). A negative correlation between weight gain and duration of treatment was reported before (12). weight gain is seen more in epileptic patients over 10 yr old (13). In contrast, no association was found between weight gain and age, gender, and drug dose in another study (14), which is also consistent with our findings.
In a clinical trial on epileptic children, increased appetite was reported in all of their subjects with marked weight gain (15 (17). Tremor is commonly reported as a side effect of VPA (17) occurring in 1%-6% of patients (4) and is known to be dose dependent (18). Bruxism and myoclonus are rarely reported in the literature as side effects of VPA (1,19).
We found enuresis in 8.1% of our patients.
Enuresis due to VPA intake is less being addressed in the literature (18). In a study, 72 epileptic patients ranging from 2 to 15 yr were on longterm VPA therapy and reported enuresis in 17 of them (24%), which stopped after discontinuation of the drug. Age was the only factor introduced as the predicting factor for enuresis in this study (18). Moreover, Egger and Brett reported enuresis in 7% of their study group (100 subjects) (20).
We confirm previous findings on the frequency of enuresis after VPA therapy, but after a short-term period, however, we found no association between enuresis and age. Enuresis was a new finding in our patients and they did not have history of enuresis due to seizures.
Hair loss was reported by 6.7% of our patients.
Several studies have addressed the possible effects of VPA on hair growth, such as alopecia, thinning hair, and color change (4,21). The occurrence of this condition has been reported from 3.5% to 11% in previous studies (21). Hair loss due to VPA is usually scattered, without any scars, occurring 3 to 6 months after starting VPA, and is suggested to be associated with higher doses of the medication in a few studies (21). Only one case (0.5%) complained of skin rash in our study. Skin rash is a rarely reported complication of VPA, mostly seen in combination therapies and is disappeared after drug discontinuation (4,22).
VPA might impair color perception significantly (23). A study on adolescents on VPA monotherapy showed that VPA can significantly affect central and para-central color vision after a short-term period (24). Ophthalmologic examination of these patients is recommended in case ophthalmic symptoms develop (24). Two of our patients (1%) complained of abnormal color vision during their treatment. The complication was reversed by VPA discontinuation. Our patients described their condition as seeing objects with abnormal colors or dominancy of certain colors. Considering the reversibility of these symptoms, it seems not to be a serious complication of VPA.
We found thrombocytopenia in 1% of our patients. Thrombocytopenia is a dose-dependent complication of VPA (1,4). This condition has been reported in a wide range of 1% to 32% in patients with different age groups and is known as the most common hematologic side effect of VPA (1,18,25,26). Thrombocytopenia is reported more frequently due to multiple drug treatment, being female, and initial thrombocytopenia (27).
Children are more prone to thrombocytopenia because of using higher doses of the drug compared to adults. Reduction or discontinuation of VPA results in increasing platelet counts in the next few days in these patients (25).